Our long-term goal is to test the hypothesis that growth factors such as the glial cell line-derived neurotrophic factor (GDNF) counteract the adverse actions of alcohol and thus prevent or delay the development of alcohol addiction. In the first round of funding we found that the activation of the GDNF pathway in the midbrain dopaminergic ventral tegmental area (VTA) rapidly attenuates the motivation for, and relapse to, ethanol consumption. Using a multidisciplinary approach, we plan to elucidate the mechanism underlying the actions of GDNF to reduce consumption of ethanol. In Aim 1, we will examine whether GDNF in the VTA possesses intrinsic rewarding or stimulant properties. In Aim 2, we will determine whether GDNF adjusts the excitability of VTA neurons in a rat model of long-term excessive ethanol consumption. In Aim 3 we will test if GDNF in the VTA modifies the neuroadaptations in dopamine levels in the nucleus accumbens resulting from excessive ethanol consumption. In Aim 4, we will elucidate the molecular mechanism responsible for GDNF's action to attenuate ethanol-drinking behaviors. Alcoholism is a devastating disease that manifests itself in uncontrolled consumption. Identifying signaling pathways that inhibit this phenotype, such as the ones activated by GDNF, are therefore of great interest, as this will likely lead to the identification of new targets for medication development to treat alcoholism, and may also lead to the identification of genetic risk factors for the disease. PUBLIC HEALTH RELEVANCE: Alcoholism is a devastating disease that affects approximately 14 million people per year in the USA alone. Unfortunately, only limited numbers of drugs are currently approved by the FDA to treat adverse phenotypes associated with the disease. Therefore, there is a great need to identify novel targets for medication development. We found that the growth factor GDNF is a negative regulator of alcohol-drinking behaviors and relapse. Therefore, GDNF and its downstream effector proteins are potential drug targets to treat alcoholism. Here, we plan to elucidate the mechanism by which GDNF regulates alcohol's actions. Results generated from these studies may lead to development of novel, selective agents to treat alcohol abuse.